Obesity is a chronic disease and as such it needs for a long-term treatment. Obesity is essentially the consequence of a long term positive energy balance. Positive energy balance occurs when energy intake is higher than energy expenditure. In particular, excessive fat intake plays a very important role in the development of obesity.
The main therapy that needs to be considered initially to treat obesity is an improvement in dietary habits of the patient and increasing physical activity or exercise. Nevertheless, when the problem of obesity is not solved by this strategy or it is associated with other disorders, pharmacological treatment is required. Most of drugs used for the treatment of obesity operate diminishing fat consumption by a mechanism of suppression food intake, these drugs act at a level of the Central Nervous System and have an anorexigenic effect, (i.e they reduce hunger) thus they cannot be used for a long-term treatment.
Obesity being a disease that may unleash many other diseases including diabetes, hypertension and atherosclerosis, a huge amount of research has been developed to obtain biomolecules that help to solve the problem. Recently, inhibitors of the lipase enzyme are the molecules most used with this purpose.
This type of drugs diminish fat absorption by inhibiting the activity of pancreatic lipase enzyme avoiding fat hydrolysis into their most singles components, promoting their elimination without being absorbed.
Lipase enzymes hydrolyze ester bonds from lipids, releasing fatty acids and glycerol. In Human beings triglycerides digestion is carried out mainly by the action of three enzymes: gastric lipase, carboxyl ester lipase and pancreatic lipase. Released fatty acids are incorporated into phospholipids micelles and eventually get into blood stream as chylomicrons.
Lypase is a water-soluble enzyme, contrasting with its substrates which are water-insoluble. Thus, substrates must be emulsified with bile salts to allow their hydrolysis by lipase enzyme. In fact lipases are only active in the inter-phase oil:water, suffering an irreversible denaturalization or conformational changes required for the linkage with the substrate, producing an activated complex that later derivates in the product.
The most used lipase inhibitor is orlistat or tetrahidrolipstatin. This has a low efficiency, since only diminish fat absorption from the diet by 30%. This low efficiency is due to its mechanism of action since being a competitive inhibitor it needs to act directly in the active place of the enzyme, which is complicated by the complex system formed during the fat digestion process.
Although in vitro orlistat fully inhibits pancreatic lipase activity, its efficacy in vivo is affected mainly by the system on which fat digestion takes place, characterized by discontinuous system of oil emulsified in water.
U.S. Pat. No. 4,598,089 describes the use of lipstatin and tetrahydrolipstatin for the prevention and treatment of obesity and hyperlipidemy. Lipstatin and tetrahydrolipstatin are powerful inhibitors of gastric and pancreatic lipase, with their use it has been demonstrated a reduction in fat absorption of up to 30% of dietary fat.
These molecules inhibit lipase in a competitive and irreversible manner, to carry out the inhibitory function they require to be in contact with the active site of the enzyme, which could be complicated by the complex system formed during fat digestion. Lipstatin is normally used at a dose of 120 mg per meal, an increment in dosing does not increase efficacy, but does increase the experience of adverse effects.
Gargouri et al (Gargouri et al., “Studies on the inhibition of pancreatic and microbial lipases by soybean proteins”; J Lipid Res., 25: 1214-1221 1984) reported that some proteins such as serum albumin, β-lactoglobulin, and certain soybean proteins inhibit some lipases activity. These molecules do not act directly on the enzyme, but they modify the lipid emulsion, avoiding the contact of the enzyme with the substrate.
Wang y Huang (Wang y Huang “Inhibitors of lipase activities in soybean and other oil seeds”; Plant Physiol., 76: 929-934 1984), Tani et al (Tani et al., “Purification and characterization of proteinous inhibitor of lipase from wheat flour”; J Agric Food Chem., 42:2382-2385 1994) early reported the presence in some grains of basic proteins with inhibitory lipase activity, and later Miyazaki et al in the US patent (U.S. Pat. No. 5,411,9569) described some basic proteins that could be used as lipase inhibitors for obesity treatment.
One of the main side effects observed when lipase inhibitors are used for obesity treatment is the sudden oily anal leakage, which happens as a result of the physical separation of the not absorbed liquid fat from the fecal matter in the intestine. Several inventions have been developed with the purpose of prevent this effect.
Some patents have suggested a combination of the lipase inhibitor with insoluble fibers to significantly reduce side effects. The problem with this approach is the adequate selection of a polymer or fiber.
Smidt et al. In the U.S. Pat. No. 6,703,369 describe the invention of a chewable product containing soluble fiber, preferably methyl-cellulose and a lipstatine derivative, preferably orlistat. Cellulose addition helps to control undesirable side effects of lipstatine consumption as lipase inhibitor.
Josefiak in the U.S. Pat. No. 6,726,906 disclosed a method to treat obesity and high triglycerides concentration in blood by means of a reduction of fat absorption. This method comprised oral administration of a fat trapping polymer in combination with a lipase inhibitor lipstatin or tetrahidrolipstatin, claiming that the fat trapping polymer helps to eliminate typical adverse side effects such as steatorrhea and other gastrointestinal problems that occur with the administration of lipase inhibitors.
Polyacrilamide as such is non-toxic, however, after polymerization, this polymer can have non-polymerize residues which could be in the range of 0.05% to 5.0% of the final product. It is known that non-polymerized acrilamide residues are highly neurotoxic and highly water soluble and can be absorbed by any exposure route such as respiratory or digestive or even by dermal exposure. (Windholz, Merck Index 10th ed. 1989; Croll et al., “Residues of acrylamide in water”; Water Res., 8,989-993 1974.
Other document patents disclosed the use of insoluble fiber with this purpose (Smidt et al., U.S. Pat. No. 6,703,369; Hug et alt., Niazi U.S. Pat. No. 6,251,421), in these cases the action of the fibers is more physical and mechanical than chemical and therefore a huge amount is required to carry out an adequate function.
Other patents suggest the use of gums acting as fat-trapping polymers such as xantana gum (Hug et al., U.S. Pat. No. 6,358,522) and konjac (Bailly U.S. Pat. No. 6,030,953) however, these compounds can act also as emulsifiers and as such they create proper conditions for lipase activity promoting fat absorption.
Bailly et al (U.S. Pat. No. 6,030,953) developed an invention for the treatment of obesity. Particularly, this invention is composed of lipase inhibitor (orlistat or tetrahidrolipstatina) and konjac or glucomanan. The use of konjac or glucomanan prevents the gastrointestinal problems produced by the lipase inhibitor of lipasa that have been already discussed.
Hug et al (U.S. Pat. No. 6,358,522) based on remarks of the U.S. Pat. No. 5,447,953, in which it was demonstrated that the combination of lipase inhibitors with insoluble fiber, make it possible to diminish fat absorption higher than that observed by the administration of the inhibitor alone; developed a pharmaceutical composition which comprises the administration of a lipase inhibitor (orlistat) together with a food grade hydrocolloid with the purpose of diminishing the adverse effects of the lipase inhibitor. Such hydrocolloid was selected from the group of natural or semi-synthetic polysaccharides such as metylcellulose, xantana gum, Psyllium plantago or combination of them.
The sheath of the Psyllium plant has been used in traditional medicine for more than 60 years. It is obtained from the seed or sheets of the Plantago ovata plant. In the United States it is used as laxative due to its absorbing water capability. It acts mainly through a mechanical effect trapping the colonic content reducing intestinal transit time. Niazi (U.S. Pat. No. 6,251,421) used the fiber of Psyllium in combination with a lipase inhibitor (orlistat) in a pharmaceutical composition to diminish fat absorption. The pharmaceutical composition reduces the absorption of fat through the inhibition of gastrointestinal lipase.
The main disadvantage of all preparations containing soluble fiber is related to the huge amount of fiber that has to be supplied to produce the effect claimed in the patents (up to 10 g or more).
Also it has been proposed the use of gums as xantan gum and konjac gum, nevertheless, these gums have a recognized capacity as emulsifier and create a proper environment for the function of lipasa, as it has been documented by (Tsujita et to., “Studies on the inhibition of pancreatic carboxilester lipase by protamine”; J Lipid Animal., 37: 1481-1487 1996).
There exist other preparations that have suggested the use of crystalline cellulose and metyl-cellulose, nevertheless their fat-trapping effect is lower as compared with those of the polymer suggested here (Bailly et to., U.S. Pat. No. 6,030,953).